Submissions for variant NM_002474.3(MYH11):c.2496G>C (p.Trp832Cys)

gnomAD frequency: 0.00005  dbSNP: rs369196744

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000157331	SCV000207068	uncertain significance	Marfan syndrome	2015-11-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458059	SCV000543716	uncertain significance	Aortic aneurysm, familial thoracic 4	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 839 of the MYH11 protein (p.Trp839Cys). This variant is present in population databases (rs369196744, gnomAD 0.008%). This missense change has been observed in individual(s) with Marfan syndrome (this individual also carried a pathogenic FBN1 variant) and/or thoracic aortic aneurysm and dissection (PMID: 25944730; internal data). ClinVar contains an entry for this variant (Variation ID: 180417). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH11 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001181078	SCV001346153	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 839 of the MYH11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with Marfan syndrome and thoracic aortic aneurysm, who also carried a pathogenic c.4210+1G>A variant in the FBN1 gene (Robertson et al., 2015). This variant has been identified in 5/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
AiLife Diagnostics, AiLife Diagnostics	RCV002223796	SCV002502275	uncertain significance	not provided	2021-12-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001181078	SCV002740909	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2022-05-31	criteria provided, single submitter	clinical testing	The p.W832C variant (also known as c.2496G>C), located in coding exon 19 of the MYH11 gene, results from a G to C substitution at nucleotide position 2496. The tryptophan at codon 832 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant co-occurred with a frameshift variant in the FBN1 gene in an individual reported to have Marfan syndrome (Wooderchak-Donahue W et al. Am J Med Genet A, 2015 Aug;167A:1747-57). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV002223796	SCV003924667	uncertain significance	not provided	2023-05-04	criteria provided, single submitter	clinical testing	Has been reported in a patient with Marfan syndrome, who also carried a pathogenic variant in the FBN1 gene (Wooderchak-Donahue et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25944730)
All of Us Research Program, National Institutes of Health	RCV001181078	SCV004823559	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-07-13	criteria provided, single submitter	clinical testing	This missense variant replaces tryptophan with cysteine at codon 839 of the MYH11 protein. Computational prediction tools indicate that this variant has a deleterious impact on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with Marfan syndrome, who also carried a pathogenic truncation variant in the FBN1 gene (PMID: 25944730). This variant has also been reported in one individual affected with inherited thoracic aortic aneurysm disease, who also carried a pathogenic c.4210+1G>A variant in the FBN1 gene (doi:10.1016/j.hlc.2015.06.677). This variant has been identified in 5/282828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700487	SCV005202943	likely benign	not specified	2024-07-23	criteria provided, single submitter	clinical testing	Variant summary: MYH11 c.2517G>C (p.Trp839Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.1e-05 in 1614046 control chromosomes. The observed variant frequency is approximately 5-fold of the estimated maximal expected allele frequency for a pathogenic variant in MYH11 causing Thoracic Aortic Aneurysms And Dissections phenotype (1.3e-05). c.2517G>C has been reported in the literature in an individual with a clinical diagnosis of Marfan Syndrome who also had a co-occurring pathogenic variant in FBN1 (c.7254dupT, p.Val2419CysfsX3), providing supporting evidence for a benign role (Wooderchak-Donahue_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 25944730).ClinVar contains an entry for this variant (Variation ID: 180417). Based on the evidence outlined above, the variant was classified as likely benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000458059	SCV005400196	uncertain significance	Aortic aneurysm, familial thoracic 4	2023-07-16	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with megacystis-microcolon-intestinal hypoperistalsis syndrome 2 (MMIHS; MIM#619351). The disease mechanism for chronic intestinal pseudo-obstruction (CIPO), also known as visceral myopathy 2 (MIM#619350), and aortic aneurysm, familial thoracic 4 (AAFT; MIM#132900) is unclear, however loss of function and dominant negative have been suggested, respectively (PMID: 31944481). (I) 0108 - This gene is associated with both recessive and dominant disease. MMIHS is an autosomal recessive form of disease caused by both missense variants and those resulting in a premature termination codon. AAFT is autosomal dominant and has been reported in patients with splice, missense and inframe deletion variants. CIPO is autosomal dominant and has only been reported in patients with protein elongation variants exclusive to isoform SM2 (PMIDs: 31389005, 31944481). (I) 0112 - The aortic aneurysm associated with this gene has incomplete penetrance (PMIDs: 17666408, 22968129). (I) 0200 - Variant is predicted to result in a missense amino acid change from tryptophan to cysteine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2 & v3) <0.001 (9 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS by multiple clinical testing laboratories, including in two individuals with aortic aneurysm or mildly dilated ascending aorta, three individuals with Ehlers Danlos syndrome or “connective tissue and skeletal symptoms”, and multiple individuals without thoracic aortic aneurysm and aortic dissection (ClinVar, personal communication). It has also been reported as a VUS in two individuals with Marfan syndrome, each of whom also had a disease-causing FBN1 variant (PMID: 25944730; ClinVar, personal communication). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign